The discovery by Albert Hofmann more than fifty years ago of the hallucinogenic effects of LSD irreversibly altered the course of both biological psychiatry and popular culture. Hallucinogens of all types are subject to widespread and increasing abuse by adolescents and young adults in this country. For example, in 1998 use of hallucinogens exceeded that of cocaine in the age groups 12-17 and 18-25. Indeed, hallucinogens were more commonly ingested than tranquilizers, inhalants, and sedatives combined. Furthermore, LSD was identified in 1999 as a "club drug" in the campaign by the National Institute on Drug Abuse to alert the public to the hazards of these agents. In addition to the well recognized abuse liability of these drugs, hallucinogens are perhaps unique in that an understanding of their mechanisms of action would contribute not only to an amelioration of the burdens of illicit use but might also provide a key to solving the puzzle of psychosis, another major human affliction. The present investigations seek to characterize indoleamine hallucinogens such as LSD and phenethylamine hallucinogens as exemplified by DOM in combined behavioral, biochemical, and analytical [GC-MS] studies. Specifically, studies will also examine the neuroanatomical sites involved in hallucinogen- induced stimulus control. In addition, experiments will further characterize interactions between the serotonergic and glutamatergic systems in the brain. Finally, the mechanisms responsible for the potentiation of LSD and other hallucinogens by fluoxetine and related selective serotonin reuptake inhibitors will be examined. Taken together, the correlational use of powerful methods for the assessment of in vivo and in vitro efficacy and of brain levels of DOM and of neurotransmitters will provide new understanding of the mode of action of hallucinogens.